Natural killer cytotoxicity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a multi-site clinical assessment of ME/CFS (MCAM) sub-study.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem illness characterized by substantial reduction in function accompanied by profound unexplained fatigue not significantly relieved by rest, post-exertional malaise, and other symptoms. Reduced natural killer (NK) cell count and cytotoxicity has been investigated as a biomarker for ME/CFS, but few clinical laboratories offer the test and multi-site verification studies have not been conducted. METHODS: We determined NK cell counts and cytotoxicity in 174 (65%) ME/CFS, 86 (32%) healthy control (HC) and 10 (3.7%) participants with other fatigue associated conditions (ill control [IC]) from the Multi-Site Clinical Assessment of ME/CFS (MCAM) study using an assay validated for samples shipped overnight instead of testing on day of venipuncture. RESULTS: We found a large variation in percent cytotoxicity [mean and (IQR) for ME/CFS and HC respectively, 34.1% (IQR 22.4-44.3%) and 33.6% (IQR 22.9-43.7%)] and no statistically significant differences between patients with ME/CFS and HC (p-value = 0.79). Analysis stratified on illness domain measured with standardized questionnaires did not identify an association of NK cytotoxicity with domain scores. Among all participants, NK cytotoxicity was not associated with survey results of physical and mental well-being, or health factors such as history of infection, obesity, smoking, and co-morbid conditions. CONCLUSION: These results indicate this assay is not ready for clinical implementation and studies are needed to further explore immune parameters that may be involved in the pathophysiology of ME/CFS.

Cardiopulmonary, metabolic, and perceptual responses during exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Multi-site Clinical Assessment of ME/CFS (MCAM) sub-study.

BACKGROUND: Cardiopulmonary exercise testing has demonstrated clinical utility in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, to what extent exercise responses are independent of, or confounded by, aerobic fitness remains unclear. PURPOSE: To characterize and compare exercise responses in ME/CFS and controls with and without matching for aerobic fitness. METHODS: As part of the Multi-site Clinical Assessment of ME/CFS (MCAM) study, 403 participants (n = 214 ME/CFS; n = 189 controls), across six ME/CFS clinics, completed ramped cycle ergometry to volitional exhaustion. Metabolic, heart rate (HR), and ratings of perceived exertion (RPE) were measured. Ventilatory equivalent ([Formula: see text], [Formula: see text]), metrics of ventilatory efficiency, and chronotropic incompetence (CI) were calculated. Exercise variables were compared using Hedges' g effect size with 95% confidence intervals. Differences in cardiopulmonary and perceptual features during exercise were analyzed using linear mixed effects models with repeated measures for relative exercise intensity (20-100% peak [Formula: see text]). Subgroup analyses were conducted for 198 participants (99 ME/CFS; 99 controls) matched for age (±5 years) and peak [Formula: see text] (~1 ml/kg/min-1). RESULTS: Ninety percent of tests (n = 194 ME/CFS, n = 169 controls) met standard criteria for peak effort. ME/CFS responses during exercise (20-100% peak [Formula: see text]) were significantly lower for ventilation, breathing frequency, HR, measures of efficiency, and CI and significantly higher for [Formula: see text], [Formula: see text] and RPE (p<0.05adjusted). For the fitness-matched subgroup, differences remained for breathing frequency, [Formula: see text], [Formula: see text], and RPE (p<0.05adjusted), and higher tidal volumes were identified for ME/CFS (p<0.05adjusted). Exercise responses at the gas exchange threshold, peak, and for measures of ventilatory efficiency (e.g., [Formula: see text]) were generally reflective of those seen throughout exercise (i.e., 20-100%). CONCLUSION: Compared to fitness-matched controls, cardiopulmonary responses to exercise in ME/CFS are characterized by inefficient exercise ventilation and augmented perception of effort. These data highlight the importance of distinguishing confounding fitness effects to identify responses that may be more specifically associated with ME/CFS.

Physiological assessment of orthostatic intolerance in chronic fatigue syndrome.

BACKGROUND: Orthostatic intolerance-OI is common in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-ME/CFS. We used a 10-min passive vertical lean test as orthostatic challenge-OC and measured changes in vitals and end tidal CO2 (eTCO2). An abnormal physiologic response to OC was identified in 60% of the 63 patients evaluated from one to three times over several years. Hypocapnia, either resting or induced by OC, was the most frequent abnormality, followed by postural orthostatic tachycardia. OBJECTIVE: Evaluate the physiologic response of patients with ME/CFS to a standardized OC. DESIGN: Respiratory and heart rate, blood pressure and eTCO2 were recorded twice at the end of 10-min supine rest and then every minute during the 10-min lean. Hypocapnia was eTCO2 ≤ 32 mmHg. Orthostatic tachycardia was heart rate increase ≥ 30 beats per minute compared with resting or ≥ 120 BPM. Orthostatic hypotension was decreased systolic pressure ≥ 20 mmHg from baseline. Tachypnea was respiratory rate of  ≥ 20 breaths per minute-either supine or leaning. Questionnaire data on symptom severity, quality of life and mood were collected at visit #2. PATIENTS: 63 consecutive patients fulfilling the 1994 case definition for CFS underwent lean testing at first visit and then annually at visit 2 (n = 48) and 3 (n = 29). MEASURES: Supine hypocapnia; orthostatic tachycardia, hypocapnia or hypotension. RESULTS: The majority of ME/CFS patients (60.3%, 38/63) had an abnormality detected during a lean test at any visit (51%, 50% and 45% at visits 1, 2 and 3, respectively). Hypocapnia at rest or induced by OC was more common and more likely to persist than postural orthostatic tachycardia. Anxiety scores did not differ between those with and without hypocapnia. CONCLUSIONS: The 10-min lean test is useful in evaluation of OI in patients with ME/CFS. The most frequent abnormality, hypocapnia, would be missed without capnography.

Population-Based Assessment of HPV Genotype-Specific Cervical Cancer Survival: CDC Cancer Registry Sentinel Surveillance System.

Background: Human papillomavirus (HPV) genotype influences the development of invasive cervical cancer (ICC); however, there is uncertainty regarding the association of HPV genotype with survival among ICC patients. Methods: Follow-up data were collected from 693 previously selected and HPV-typed ICC cases that were part of the Centers for Disease Control and Prevention Cancer Registry Surveillance System. Cases were diagnosed between 1994 and 2005. The Kaplan-Meier method was used to estimate five-year all-cause survival. A multivariable Cox proportional hazards model was used to estimate the effect of HPV genotype on survival after adjusting for demographic, tumor, and treatment characteristics. Results: Five-year all-cause survival rates varied by HPV status (HPV 16: 66.9%, HPV 18: 65.7%, HPV 31/33/45/52/58: 70.8%, other oncogenic HPV genotypes: 79.0%, nononcogenic HPV: 69.3%, HPV-negative: 54.0%). Following multivariable adjustment, no statistically significant survival differences were found for ICC patients with HPV 16-positive tumors compared with women with tumors positive for HPV 18, other oncogenic HPV types, or HPV-negative tumors. Women with detectable HPV 31/33/33/45/52/58 had a statistically significant 40% reduced hazard of death at five years (95% confidence interval [CI] = 0.38 to 0.95), and women who tested positive for nononcogenic HPV genotypes had a statistically significant 57% reduced hazard of death at five years (95% CI = 0.19 to 0.96) compared with women with HPV 16 tumors. Few statistically significant differences in HPV positivity, tumor characteristics, treatment, or survival were found by race/ethnicity. Conclusions: HPV genotype statistically significantly influenced five-year survival rates among women with ICC; however, screening and HPV vaccination remain the most important factors to improve patient prognosis and prevent future cases.

Multi-Site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM): Design and Implementation of a Prospective/Retrospective Rolling Cohort Study.

In the Multi-Site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM), we relied on expert clinician diagnoses to enroll patients from 7 specialty clinics in the United States in order to perform a systematic collection of data on measures of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). Healthy persons and those with other illnesses that share some features with ME/CFS were enrolled in comparison groups. The major objectives were to: 1) use standardized questionnaires to measure illness domains of ME/CFS and to evaluate patient heterogeneity overall and between clinics; 2) describe the course of illness, identify the measures that best correlate with meaningful clinical differences, and assess the performances of questionnaires as patient/person-reported outcome measures; 3) describe prescribed medications, orders for laboratory and other tests, and management tools used by expert clinicians to care for persons with ME/CFS; 4) collect biospecimens for future hypothesis testing and for evaluation of morning cortisol profiles; and 5) identify measures that best distinguish persons with ME/CFS from those in the comparison groups and detect subgroups of persons with ME/CFS who may have different underlying causes. Enrollment began in 2012 and is planned to continue in multiple stages through 2017. We present the MCAM methods in detail, along with an initial description of the 471 patients with ME/CFS who were enrolled in stage 1.

Assessment of ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome): A Case Study for Health Care Providers.

INTRODUCTION: Over a million adults in the U.S. are affected by chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME). A debilitating illness, ME/CFS is accompanied by profound fatigue that is not relieved by rest and affects daily activities. Symptoms include postexertional malaise, cognitive problems, unrefreshing sleep, and pain. This course provides tools to teach medical, physician assistant, and nursing students to recognize, diagnose, and manage patients with ME/CFS. METHODS: The student is expected to view the provider-to-provider video and the PowerPoint slide curriculum, which describe the steps for evaluation. The video depicts two physicians conferring about ME/CFS and addresses the challenges of making a diagnosis. The slide curriculum shows the different ME/CFS symptoms and case definitions and how to apply them using a case study. Medical, physician assistant, and nursing students were recruited to evaluate the course and viewed it either online or in a campus education center. RESULTS: Results showed that students met learning objectives and showed increases from pre- to posttest evaluation in their understanding of the difficulties of diagnosing ME/CFS and managing the illness. In addition to knowledge, student attitudes towards ME/CFS changed, with more empathy towards patients and the awareness that ME/CFS requires frequent communication and reevaluation of patients' symptoms. DISCUSSION: Strategies of how to manage ME/CFS for the patient and manage time constraints during visits with ME/CFS patients are discussed.

US assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines.

BACKGROUND: This study sought to determine the prevaccine type-specific prevalence of human papillomavirus (HPV)-associated cancers in the United States to evaluate the potential impact of the HPV types in the current and newly approved 9-valent HPV vaccines. METHODS: The Centers for Disease Control and Prevention partnered with seven US population-based cancer registries to obtain archival tissue for cancers diagnosed from 1993 to 2005. HPV testing was performed on 2670 case patients that were fairly representative of all participating cancer registry cases by age and sex. Demographic and clinical data were evaluated by anatomic site and HPV status. Current US cancer registry data and the detection of HPV types were used to estimate the number of cancers potentially preventable through vaccination. RESULTS: HPV DNA was detected in 90.6% of cervical, 91.1% of anal, 75.0% of vaginal, 70.1% of oropharyngeal, 68.8% of vulvar, 63.3% of penile, 32.0% of oral cavity, and 20.9% of laryngeal cancers, as well as in 98.8% of cervical cancer in situ (CCIS). A vaccine targeting HPV 16/18 potentially prevents the majority of invasive cervical (66.2%), anal (79.4%), oropharyngeal (60.2%), and vaginal (55.1%) cancers, as well as many penile (47.9%), vulvar (48.6%) cancers: 24 858 cases annually. The 9-valent vaccine also targeting HPV 31/33/45/52/58 may prevent an additional 4.2% to 18.3% of cancers: 3944 cases annually. For most cancers, younger age at diagnosis was associated with higher HPV 16/18 prevalence. With the exception of oropharyngeal cancers and CCIS, HPV 16/18 prevalence was similar across racial/ethnic groups. CONCLUSIONS: In the United States, current vaccines will reduce most HPV-associated cancers; a smaller additional reduction would be contributed by the new 9-valent vaccine.

CDC grand rounds: Reducing the burden of HPV-associated cancer and disease.

Human papillomavirus (HPV) infection is the most common sexually transmitted infection in men and women in the United States. Most sexually active persons will acquire HPV in their lifetime. Recent data indicate that approximately 79 million persons are currently infected with HPV, and 14 million persons are newly infected each year in the United States.

Would young women attending sexually transmitted disease clinics benefit from human papillomavirus vaccination? An assessment of human papillomavirus DNA and seropositivity from human papillomavirus sentinel surveillance, 2003-2005.

BACKGROUND: There are limited data on the proportion who have been exposed to vaccine-type human papillomavirus (HPV) among women attending sexually transmitted disease (STD) clinics; this information could inform the potential benefits of HPV vaccination for women attending this venue. METHODS: Human papillomavirus surveillance was conducted in STD clinics in Baltimore, MD; Boston, MA; Denver, CO; Los Angeles, CA; and Seattle, WA, among women receiving cervical cancer screening from January 2003 to December 2005. The women had specimens collected for cervical cytology HPV testing by L1 consensus polymerase chain reaction testing and serologic assessment for HPV 6, 11, 16, and 18 using the competitive Luminex immunoassay. Results from 880 women with adequate specimens were included. Women were HPV naïve if they were both HPV DNA negative and seronegative for a specific HPV type. RESULTS: One hundred seventy women (19.3%) had HPV 16, 18, 6, or 11 DNA, and 418 (47.5%) were HPV 16, 18, 6, or 11 seropositive. Four hundred ten (46.6%) women were naïve to all 4 types, 570 (64.8%) were naïve to both HPV 16 and 18, and 545 (61.9%) were naïve to both HPV 6 and 11. Almost all (99.3%) women were naïve to at least 1 vaccine HPV type. CONCLUSIONS: Almost half of young women age eligible for HPV vaccine and attending STD clinics were naïve to all 4 HPV types, and more than half were naïve to both HPV 16 and 18. This assessment suggests that most young women attending this venue might benefit from HPV vaccination.

Prevalence of HPV types in cervical specimens from an integrated healthcare delivery system: baseline assessment to measure HPV vaccine impact.

PURPOSE: Two human papillomavirus (HPV) vaccines are available to prevent cervical cancer. One early measure of HPV vaccine impact would be a reduction in vaccine-related HPV types (HPV 6, 11, 16, or 18, or HPV 16, 18) in cervical samples from young women. We aimed to assess feasibility of specimen collection and baseline HPV prevalence in an integrated healthcare delivery system. METHODS: Residual cervical specimens collected during routine cervical cancer screening (2006-2008) were retained consecutively from eligible females aged 11-29 years, stratified by age group. Specimens were evaluated for 37 HPV genotypes using the Roche Linear Array assay. RESULTS: Of 10,124 specimens submitted, 10,103 (99 %) were adequate for HPV testing. Prevalence of HPV 6, 11, 16, or 18 genotype was 11.4 % overall and was the highest in the youngest age group (18.1 % in the 11-19-year-olds, 12.5 % in the 20-24-year-olds, and 7.0 % in the 25-29-year-olds). CONCLUSIONS: HPV types 6, 11, 16, or 18 prevalence could be measured over time to assess early HPV vaccine impact using residual specimens from an integrated healthcare delivery system, particularly if sampling focused on young women.

Perception versus polysomnographic assessment of sleep in CFS and non-fatigued control subjects: results from a population-based study.

BACKGROUND: Complaints of unrefreshing sleep are a prominent component of chronic fatigue syndrome (CFS); yet, polysomnographic studies have not consistently documented sleep abnormalities in CFS patients. We conducted this study to determine whether alterations in objective sleep characteristics are associated with subjective measures of poor sleep quality in persons with CFS. METHODS: We examined the relationship between perceived sleep quality and polysomnographic measures of nighttime and daytime sleep in 35 people with CFS and 40 non-fatigued control subjects, identified from the general population of Wichita, Kansas and defined by empiric criteria. Perceived sleep quality and daytime sleepiness were assessed using clinical sleep questionnaires. Objective sleep characteristics were assessed by nocturnal polysomnography and daytime multiple sleep latency testing. RESULTS: Participants with CFS reported unrefreshing sleep and problems sleeping during the preceding month significantly more often than did non-fatigued controls. Participants with CFS also rated their quality of sleep during the overnight sleep study as significantly worse than did control subjects. Control subjects reported significantly longer sleep onset latency than latency to fall asleep as measured by PSG and MSLT. There were no significant differences in sleep pathology or architecture between subjects with CFS and control subjects. CONCLUSION: People with CFS reported sleep problems significantly more often than control subjects. Yet, when measured these parameters and sleep architecture did not differ between the two subject groups. A unique finding requiring further study is that control, but not CFS subjects, significantly over reported sleep latency suggesting CFS subjects may have an increased appreciation of sleep behaviour that may contribute to their perception of sleep problems.

Psychometric properties of the CDC Symptom Inventory for assessment of chronic fatigue syndrome.

OBJECTIVES: Validated or standardized self-report questionnaires used in research studies and clinical evaluation of chronic fatigue syndrome (CFS) generally focus on the assessment of fatigue. There are relatively few published questionnaires that evaluate case defining and other accompanying symptoms in CFS. This paper introduces the self-report CDC CFS Symptom Inventory and analyzes its psychometric properties. METHODS: One hundred sixty-four subjects (with CFS, other fatiguing illnesses and non fatigued controls) identified from the general population of Wichita, Kansas were enrolled. Evaluation included a physical examination, a standardized psychiatric interview, three previously validated self-report questionnaires measuring fatigue and illness impact (Medical Outcomes Survey Short-Form-36 [MOS SF-36], Multidimensional Fatigue Inventory [MFI], Chalder Fatigue Scale), and the CDC CFS Symptom Inventory. Based on theoretical assumptions and statistical analyses, we developed several different Symptom Inventory scores and evaluated them on their ability to differentiate between participants with CFS and non-fatigued controls. RESULTS: The Symptom Inventory had good internal consistency and excellent convergent validity. A Total score (all symptoms), Case Definition score (CFS case defining symptoms) and Short Form score (6 symptoms with minimal correlation) differentiated CFS cases from controls. Furthermore, both the Case Definition and Short Form scores distinguished people with CFS from fatigued subjects who did not meet criteria for CFS. CONCLUSION: The Symptom Inventory appears to be a reliable and valid instrument to assess symptoms that accompany CFS. It is a positive addition to existing instruments measuring fatigue because it allows other dimensions of the illness to be assessed. Further research is needed to confirm and replicate the current findings in a normative population.

Sleep assessment in a population-based study of chronic fatigue syndrome.

BACKGROUND: Chronic fatigue syndrome (CFS) is a disabling condition that affects approximately 800,000 adult Americans. The pathophysiology remains unknown and there are no diagnostic markers or characteristic physical signs or laboratory abnormalities. Most CFS patients complain of unrefreshing sleep and many of the postulated etiologies of CFS affect sleep. Conversely, many sleep disorders present similarly to CFS. Few studies characterizing sleep in unselected CFS subjects have been published and none have been performed in cases identified from population-based studies. METHODS: The study included 339 subjects (mean age 45.8 years, 77% female, 94.1% white) identified through telephone screen in a previously described population-based study of CFS in Wichita, Kansas. They completed questionnaires to assess fatigue and wellness and 2 self-administered sleep questionnaires. Scores for five of the six sleep factors (insomnia/hypersomnia, non-restorative sleep, excessive daytime somnolence, sleep apnea, and restlessness) in the Centre for Sleep and Chronobiology's Sleep Assessment Questionnaire (SAQ) were dichotomized based on threshold. The Epworth Sleepiness Scale score was used as a continuous variable. RESULTS: 81.4% of subjects had an abnormality in at least one SAQ sleep factor. Subjects with sleep factor abnormalities had significantly lower wellness scores but statistically unchanged fatigue severity scores compared to those without SAQ abnormality. CFS subjects had significantly increased risk of abnormal scores in the non-restorative (adjusted odds ratio [OR] = 28.1; 95% confidence interval [CI]= 7.4-107.0) and restlessness (OR = 16.0; 95% CI = 4.2-61.6) SAQ factors compared to non-fatigued, but not for factors of sleep apnea or excessive daytime somnolence. This is consistent with studies finding that, while fatigued, CFS subjects are not sleepy. A strong correlation (0.78) of Epworth score was found only for the excessive daytime somnolence factor. CONCLUSIONS: SAQ factors describe sleep abnormalities associated with CFS and provide more information than the Epworth score. Validation of these promising results will require formal polysomnographic sleep studies.

Predictors of remission in juvenile-onset recurrent respiratory papillomatosis.

OBJECTIVE: To determine factors associated with remission of juvenile-onset recurrent respiratory papillomatosis (JORRP). DESIGN: Longitudinal study. SETTING: Twenty-two tertiary care centers located across the United States. STUDY PARTICIPANTS AND METHODS: The study included 165 patients diagnosed as having JORRP between January 1, 1997, and December 31, 2000. Kaplan-Meier curves and Cox proportional hazards models were used to determine associations between predictors and remission. INTERVENTIONS: Surgical excision and drug therapy. MAIN OUTCOME MEASURES: Remission of JORRP, defined as no surgical procedures for at least 1 year, as associated with age at diagnosis, drug therapy in the first year after diagnosis, number of surgical procedures in the first year after diagnosis, and number of anatomical sites of disease at diagnosis. Demographic factors (sex and race) and Medicaid status were also evaluated. RESULTS: Older age at diagnosis was positively associated with remission of JORRP (hazards ratio for every increase of 1 year in age, 1.13; 95% confidence interval, 1.03-1.23). CONCLUSIONS: Younger children were found to have persistent disease and often underwent an increased number of surgical procedures in the first year after diagnosis of JORRP. Sex and race were not important factors in determining remission.

Assessment of normal variability in peripheral blood gene expression.

Peripheral blood is representative of many systemic processes and is an ideal sample for expression profiling of diseases that have no known or accessible lesion. Peripheral blood is a complex mixture of cell types and some differences in peripheral blood gene expression may reflect the timing of sample collection rather than an underlying disease process. For this reason, it is important to assess study design factors that may cause variability in gene expression not related to what is being analyzed. Variation in the gene expression of circulating peripheral blood mononuclear cells (PBMCs) from three healthy volunteers sampled three times one day each week for one month was examined for 1,176 genes printed on filter arrays. Less than 1% of the genes showed any variation in expression that was related to the time of collection, and none of the changes were noted in more than one individual. These results suggest that observed variation was due to experimental variability.